We are interested in understanding molecular mechanisms that regulate receptor signaling at and across membranes. We continue our long-standing interest in the regulation of the Epidermal Growth Factor Receptor (EGFR) family of receptor tyrosine kinases (RTKs), and also expand our study to several other families of RTKs. Rekindling an early interest in pleckstrin homology domains, we are also investigating the role of lipid binding modules in several settings. To address these questions we use a combination of biophysical, structural, biochemical and cellular approaches.

EGFR is an important and clinically validated cancer target. Despite many years of study, there remain significant questions about the mechanism of activation of EGFR, and its dysregulation in cancer. Using X-ray crystallography as a primary tool, we have elucidated the mechanisms of action of several clinically relevant EGFR antibodies, including cetuximab and necitumumab. We have also shown that nanobodies or VHH domains, the smallest natural antigen-binding modules (from heavy chain only camelid antibodies), can inhibit EGFR either by mimicking existing antibodies or through unique mechanisms - emphasizing the power of nanobodies as possible ‘designer inhibitors’ and as tools for asking mechanistic questions about their binding targets. Current efforts in this area focus on the use of antibodies and nanobodies to understand oncogenically activated EGFR.

A subset of the oncogenically activated EGFR mutations that have been identified from patient samples lie in the extracellular region of the receptor. We currently have no molecular understanding of how these mutations activate of the receptor. To address this we are investigating, in collaboration with Mark Lemmon, how the extracellular and intracellular regions of EGFR are coupled.

(ii) RTKs with membrane proximal FNIII domains.

Mounting data indicate far more mechanistic diversity across the RTK superfamily than previously thought, and we are also interested in several other families of RTKs. In one project, we are analyzing the roles of membrane-proximal fibronectin type III (FNIII) domains (found in 23/58 RTKs, including Tie2). In collaboration with Mark Lemmon, we are trying to understand the relationship between oligomerization of Tie receptors and receptor activation state.